The primary objective of this long-standing grant remains understanding the molecular and cellular mechanisms underlying production, migration and positioning of neurons during development of the cerebral cortex. The early events that precede formation of synaptic connections determine the size and patterning of cytoarchitectonic areas. Our strategy is to conduct comparative studies of these early developmental events in mice and primates to uncover evolutionary adaptations leading to the expansion and elaboration of this structure. We hypothesize that the longer cell cycle and migratory pathways of primates predisposes them to congenital malformations during prenatal life. In Specific Aim #1 we have developed new in vitro and in vivo approaches to analyze regulation of neuronal production and phenotype specification. We propose to examine the mode and pattern of proliferation of neural stem cells combining multi-photon microscopy and transfection methodologies. These studies will test the roles of several morphoregulatory molecules (Lis 1; Beta-catenine; Notch and its modulators) in regulation of cell cycle and diversification into neural and glial cell lines and the transition of neuronal stem cells from the active stage to dormancy. Specific Aim #2 is focused on normal and abnormal neuronal migration. We will examine interneuron migration from the ganglionic eminence of the ventral telencephalon and their integration with the radially disposed neurons derived from the dorsal telencephalon in the normal and genetically perturbed forebrains of reeler and Pax6 mice. The possible effect of ultrasound on neuronal migration rate and placement will also be examined in both the murine and primate cerebral cortex, as this study may have important biomedical implications. [unreadable] [unreadable] Emphasis on the early aspects of neuronal production and proper placement in mammalian species will provide new insight into the pathogenesis of genetic and acquired cortical malformations affecting higher brain function. The proposed studies are even more pressing given the recent increase in incidence of developmental idiopathic disorders of higher brain functions such as autism, childhood epilepsy, developmental dyslexia and mental retardation, that are possibly in part attributable to neuronal misplacement during formation of the cerebral cortex. [unreadable] [unreadable]